Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Caring for children with NAFLD and navigating their care into adulthood

Nature Reviews Gastroenterology & Hepatology volume 12, pages 617–628 (2015)Cite this article

Subjects

Key Points

  • Coincident with the rise of obesity, NAFLD has become the most common cause of chronic liver injury in the industrialized world in both children and adults

  • The mainstay of treatment for both adult and paediatric NASH are diet and exercise resulting in weight loss

  • Medical treatment of NAFLD should be considered only for those patients with biopsy-proven NASH who have failed lifestyle intervention; current medical therapies lack long-term safety and efficacy data

  • Transitioning to adult care should begin in early adolescence and should be multifaceted

  • Paediatric providers should prepare patients to take an active role in their care, have an understanding of their disease, and should assess logistical and psychosocial challenges that might impair transition

  • Adult providers should be aware of the differences between paediatric and adult NAFLD to provide a smooth transition process that is integrated with the paediatric model

Abstract

NAFLD is the most common chronic liver disease in children and adults, with its prevalence closely associated with obesity and other features of the metabolic syndrome. As young adults with NAFLD transition from the paediatric care environment to adult services, establishing a coordinated model of transition to ensure ongoing and appropriate care is critical. Enabling a smooth transfer begins with an understanding of the key differences between paediatric and adult NAFLD as well as the psychosocial factors that affect older adolescents. This Review summarizes the literature on paediatric NAFLD from the past two decades with a focus on the differences in epidemiology, pathology, pathophysiology and treatment that are relevant to clinicians who transition paediatric patients to adult care. An integrated model, which employs a team of adult and paediatric providers who can address the psychosocial, cognitive and logistical challenges of transition, provides the best opportunity for a seamless and coordinated transfer to adult care.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Histologic features of NASH.
Figure 2: Characteristics associated with NAFLD in adult and paediatric patients.
Figure 3: Algorithm for the diagnosis and management of paediatric NAFLD.

Similar content being viewed by others

References

  1. Ogden, C. L., Carroll, M. D., Kit, B. K. & Flegal, K. M. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 311, 806–814 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Finkelstein, E. A., Trogdon, J. G., Cohen, J. W. & Dietz, W. Annual medical spending attributable to obesity: payer- and service-specific estimates. Health Aff. (Millwood) 28, w822–w831 (2009).

    Google Scholar 

  3. Alberti, K. G. et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120, 1640–1645 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Brunt, E. M. Pathology of nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 7, 195–203 (2010).

    Article  PubMed  Google Scholar 

  5. Fraser, A., Longnecker, M. P. & Lawlor, D. A. Prevalence of elevated alanine aminotransferase among US adolescents and associated factors: NHANES 1999–2004. Gastroenterology 133, 1814–1820 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Schwimmer, J. B. et al. Prevalence of fatty liver in children and adolescents. Pediatrics 118, 1388–1393 (2006).

    Article  PubMed  Google Scholar 

  7. Vernon, G., Baranova, A. & Younossi, Z. M. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 34, 274–285 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Patton, H. M. et al. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology 135, 1961–1971. e2 (2008).

    Article  PubMed  Google Scholar 

  9. Molleston, J. P. et al. Histological abnormalities in children with nonalcoholic fatty liver disease and normal or mildly elevated alanine aminotransferase levels. J. Pediatr. 164, 707–713. e3 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Saadeh, S. & Younossi, Z. M. The spectrum of nonalcoholic fatty liver disease: from steatosis to nonalcoholic steatohepatitis. Cleve. Clin. J. Med. 67, 96–97, 101–104 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Fishbein, M. et al. Hepatic MRI for fat quantitation: its relationship to fat morphology, diagnosis, and ultrasound. J. Clin. Gastroenterol. 39, 619–625 (2005).

    Article  PubMed  Google Scholar 

  12. Pacifico, L. et al. MRI and ultrasound for hepatic fat quantification: relationships to clinical and metabolic characteristics of pediatric nonalcoholic fatty liver disease. Acta Paediatr. 96, 542–547 (2007).

    Article  PubMed  Google Scholar 

  13. Loomba, R. et al. Ezetimibe for the treatment of nonalcoholic steatohepatitis: assessment by novel magnetic resonance imaging and magnetic resonance elastography in a randomized trial (MOZART trial). Hepatology 61, 1239–1250 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Rorat, M. et al. Liver steatosis in Polish children assessed by medicolegal autopsies. World J. Pediatr. 9, 68–72 (2013).

    Article  PubMed  Google Scholar 

  15. Yüksel, F. et al. Fatty liver disease in an autopsy series of children and adolescents. Hippokratia 16, 61–65 (2012).

    PubMed  PubMed Central  Google Scholar 

  16. Wiegand, S. et al. Obese boys at increased risk for nonalcoholic liver disease: evaluation of 16, 390 overweight or obese children and adolescents. Int. J. Obes. (Lond.) 34, 1468–1474 (2010).

    Article  CAS  Google Scholar 

  17. Boyraz, M. et al. Non-alcoholic fatty liver disease in obese children and the relationship between metabolic syndrome criteria. Obes. Res. Clin. Pract. 8, e356–e363 (2014).

    Article  PubMed  Google Scholar 

  18. Lin, Y. C., Chang, P. F., Yeh, S. J., Liu, K. & Chen, H. C. Risk factors for liver steatosis in obese children and adolescents. Pediatr. Neonatol. 51, 149–154 (2010).

    Article  PubMed  Google Scholar 

  19. Farrell, G. C., Wong, V. W. & Chitturi, S. NAFLD in Asia—as common and important as in the West. Nat. Rev. Gastroenterol. Hepatol. 10, 307–318 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Dassanayake, A. S. et al. Prevalence and risk factors for non-alcoholic fatty liver disease among adults in an urban Sri Lankan population. J. Gastroenterol. Hepatol. 24, 1284–1288 (2009).

    Article  PubMed  Google Scholar 

  21. Masarone, M., Federico, A., Abenavoli, L., Loguercio, C. & Persico, M. Nonalcoholic fatty liver: epidemiology and natural history. Rev. Recent Clin. Trials 9, 126–133 (2014).

    Article  PubMed  Google Scholar 

  22. Schwimmer, J. B., McGreal, N., Deutsch, R., Finegold, M. J. & Lavine, J. E. Influence of gender, race, and ethnicity on suspected fatty liver in obese adolescents. Pediatrics 115, e561–e565 (2005).

    Article  PubMed  Google Scholar 

  23. Lazo, M. et al. Prevalence of nonalcoholic fatty liver disease in the United States: the third national health and nutrition examination survey, 1988–1994. Am. J. Epidemiol. 178, 38–45 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Browning, J. D. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40, 1387–1395 (2004).

    Article  PubMed  Google Scholar 

  25. Clark, J. M., Brancati, F. L. & Diehl, A. M. The prevalence and etiology of elevated aminotransferase levels in the United States. Am. J. Gastroenterol. 98, 960–967 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Yang, J. D. et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 59, 1406–1414 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Jungermann, K. & Kietzmann, T. Oxygen: modulator of metabolic zonation and disease of the liver. Hepatology 31, 255–260 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Yeh, M. M. & Brunt, E. M. Pathological features of fatty liver disease. Gastroenterology 147, 754–764 (2014).

    Article  CAS  PubMed  Google Scholar 

  29. Schwimmer, J. B. et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 42, 641–649 (2005).

    Article  PubMed  Google Scholar 

  30. Carter-Kent, C. et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology 50, 1113–1120 (2009).

    Article  PubMed  Google Scholar 

  31. Takahashi, Y., Inui, A., Fujisawa, T., Takikawa, H. & Fukusato, T. Histopathological characteristics of non-alcoholic fatty liver disease in children: comparison with adult cases. Hepatol. Res. 41, 1066–1074 (2011).

    Article  PubMed  Google Scholar 

  32. Ko, J. S. et al. Clinical and histological features of nonalcoholic fatty liver disease in children. Dig. Dis. Sci. 54, 2225–2230 (2009).

    Article  PubMed  Google Scholar 

  33. Feldstein, A. E. et al. The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut 58, 1538–1544 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  35. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  36. US National Library of Medicine. ClinicalTrials.gov [online], (2015).

  37. Ekstedt, M. et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 61, 1547–1554 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Angulo, P. et al. Liver fibrosis, but no other histologic features, associates with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology http://dx.doi.org/10.1053/j.gastro.2015.04.043.

  39. Adams, L. A., Sanderson, S., Lindor, K. D. & Angulo, P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J. Hepatol. 42, 132–138 (2005).

    Article  PubMed  Google Scholar 

  40. Ekstedt, M. et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44, 865–873 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Argo, C. K., Northup, P. G., Al-Osaimi, A. M. & Caldwell, S. H. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J. Hepatol. 51, 371–379 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Wong, V. W. et al. Disease progression of non-alcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut 59, 969–974 (2010).

    Article  PubMed  Google Scholar 

  43. McPherson, S. et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J. Hepatol. 62, 1148–1155 (2015).

    Article  PubMed  Google Scholar 

  44. Singh, S. et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin. Gastroenterol. Hepatol. 13, 643–654. e1–e9 (2015).

    Article  PubMed  Google Scholar 

  45. Alkhouri, N. et al. Liver transplantation for nonalcoholic steatohepatitis (NASH) in children and young adults: the true burden of pediatric nonalcoholic fatty liver disease [abstract Su1038]. Gastroenterology 148, S-1046 (2015).

    Article  Google Scholar 

  46. Nobili, V. et al. Non-alcoholic fatty liver disease and hepatocellular carcinoma in a 7-year-old obese boy: coincidence or comorbidity? Pediatr. Obes. 9, e99–e102 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Charlton, M. R. et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 141, 1249–1253 (2011).

    Article  PubMed  Google Scholar 

  48. Altekruse, S. F., McGlynn, K. A. & Reichman, M. E. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J. Clin. Oncol. 27, 1485–1491 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Altekruse, S. F., Henley, S. J., Cucinelli, J. E. & McGlynn, K. A. Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States. Am. J. Gastroenterol. 109, 542–553 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med. 348, 1625–1638 (2003).

    Article  PubMed  Google Scholar 

  51. Alexander, J., Torbenson, M., Wu, T. T. & Yeh, M. M. Non-alcoholic fatty liver disease contributes to hepatocarcinogenesis in non-cirrhotic liver: a clinical and pathological study. J. Gastroenterol. Hepatol. 28, 848–854 (2013).

    Article  PubMed  Google Scholar 

  52. Yasui, K. et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 9, 428–433 (2011).

    Article  PubMed  Google Scholar 

  53. Dongiovanni, P., Romeo, S. & Valenti, L. Hepatocellular carcinoma in nonalcoholic fatty liver: role of environmental and genetic factors. World J. Gastroenterol. 20, 12945–12955 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jiang, C. M. et al. Non alcoholic steatohepatitis a precursor for hepatocellular carcinoma development. World J. Gastroenterol. 20, 16464–16473 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Stepanova, M. et al. Predictors of all-cause mortality and liver-related mortality in patients with non-alcoholic fatty liver disease (NAFLD). Dig. Dis. Sci. 58, 3017–3023 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Rafiq, N. et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin. Gastroenterol. Hepatol. 7, 234–238 (2009).

    Article  PubMed  Google Scholar 

  57. Ong, J. P., Pitts, A. & Younossi, Z. M. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J. Hepatol. 49, 608–612 (2008).

    Article  PubMed  Google Scholar 

  58. Caldwell, S. & Argo, C. The natural history of non-alcoholic fatty liver disease. Dig. Dis. 28, 162–168 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Must, A. et al. The disease burden associated with overweight and obesity. JAMA 282, 1523–1529 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Park, J., Morley, T. S., Kim, M., Clegg, D. J. & Scherer, P. E. Obesity and cancer—mechanisms underlying tumour progression and recurrence. Nat. Rev. Endocrinol. 10, 455–465 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dunn, W. et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am. J. Gastroenterol. 103, 2263–2271 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Lonardo, A., Ballestri, S., Targher, G. & Loria, P. Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. Expert Rev. Gastroenterol. Hepatol. 9, 629–650 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Schwimmer, J. B. et al. Longitudinal assessment of high blood pressure in children with nonalcoholic fatty liver disease. PLoS ONE 9, e112569 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Pacifico, L. et al. Nonalcoholic fatty liver disease and carotid atherosclerosis in children. Pediatr. Res. 63, 423–427 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Demirciog˘lu, F. et al. Intima-media thickness of carotid artery and susceptibility to atherosclerosis in obese children with nonalcoholic fatty liver disease. J. Pediatr. Gastroenterol. Nutr. 47, 68–75 (2008).

    Article  Google Scholar 

  66. Schenk, S., Saberi, M. & Olefsky, J. M. Insulin sensitivity: modulation by nutrients and inflammation. J. Clin. Invest. 118, 2992–3002 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Polyzos, S. A., Kountouras, J., Zavos, C. & Tsiaousi, E. The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease. Diabetes Obes. Metab. 12, 365–383 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Polyzos, S. A., Kountouras, J., Zavos, C. & Deretzi, G. The potential adverse role of leptin resistance in nonalcoholic fatty liver disease: a hypothesis based on critical review of the literature. J. Clin. Gastroenterol. 45, 50–54 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Amir, M. & Czaja, M. J. Autophagy in nonalcoholic steatohepatitis. Expert Rev. Gastroenterol. Hepatol. 5, 159–166 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Takaki, A., Kawai, D. & Yamamoto, K. Molecular mechanisms and new treatment strategies for non-alcoholic steatohepatitis (NASH). Int. J. Mol. Sci. 15, 7352–7379 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lake, A. D. et al. The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol. Sci. 137, 26–35 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Gusdon, A. M., Song, K. X. & Qu, S. Nonalcoholic fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective. Oxid. Med. Cell. Longev. 2014, 637027 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tilg, H. The role of cytokines in non-alcoholic fatty liver disease. Dig. Dis. 28, 179–185 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Sundaram, S. S. et al. Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease. J. Pediatr. 164, 699–706. e1 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Norman, D. et al. Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea. Sleep 31, 121–126 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Türkay, C. et al. Influence of obstructive sleep apnea on fatty liver disease: role of chronic intermittent hypoxia. Respir. Care 57, 244–249 (2012).

    PubMed  Google Scholar 

  77. Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Invest. 115, 209–218 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yu, Y. H. et al. Metabolic vs. hedonic obesity: a conceptual distinction and its clinical implications. Obes. Rev. 16, 234–247 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Scarpace, P. J. & Zhang, Y. Leptin resistance: a prediposing factor for diet-induced obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296, R493–R500 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Drubach, L. A. et al. Pediatric brown adipose tissue: detection, epidemiology, and differences from adults. J. Pediatr. 159, 939–944 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Rockstroh, D. et al. Direct evidence of brown adipocytes in different fat depots in children. PLoS ONE 10, e0117841 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Whitaker, R. C., Wright, J. A., Pepe, M. S., Seidel, K. D. & Dietz, W. H. Predicting obesity in young adulthood from childhood and parental obesity. N. Engl. J. Med. 337, 869–873 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Nishino, M., Hayakawa, K., Nakamura, Y., Morimoto, T. & Mukaihara, S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am. J. Roentgenol. 180, 129–134 (2003).

    Article  PubMed  Google Scholar 

  84. Cole, L. K., Jacobs, R. L. & Vance, D. E. Tamoxifen induces triacylglycerol accumulation in the mouse liver by activation of fatty acid synthesis. Hepatology 52, 1258–1265 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Lazo, M. et al. Association between endogenous sex hormones and liver fat in a multiethnic study of atherosclerosis. Clin. Gastroenterol. Hepatol. http://dx.doi.org/10.1016/j.cgh.2014.12.033.

  86. Baranova, A., Tran, T. P., Birerdinc, A. & Younossi, Z. M. Systematic review: association of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease. Aliment. Pharmacol. Ther. 33, 801–814 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Ramezani-Binabaj, M., Motalebi, M., Karimi-Sari, H., Rezaee-Zavareh, M. S. & Alavian, S. M. Are women with polycystic ovarian syndrome at a high risk of non-alcoholic fatty liver disease; a meta-analysis. Hepat. Mon. 14, e23235 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Palmer, B. F. & Clegg, D. J. The sexual dimorphism of obesity. Mol. Cell. Endocrinol. 402, 113–119 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Suzuki, A. et al. Association between puberty and features of nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 10, 786–794 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Goel, A., Gupta, M. & Aggarwal, R. Gut microbiota and liver disease. J. Gastroenterol. Hepatol. 29, 1139–1148 (2014).

    Article  PubMed  Google Scholar 

  91. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Le Roy, T. et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62, 1787–1794 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601–609 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Roh, Y. S. & Seki, E. Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J. Gastroenterol. Hepatol. 28 (Suppl. 1), 38–42 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Paolella, G. et al. Gut-liver axis and probiotics: their role in non-alcoholic fatty liver disease. World J. Gastroenterol. 20, 15518–15531 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Galvez, M. P., Pearl, M. & Yen, I. H. Childhood obesity and the built environment. Curr. Opin. Pediatr. 22, 202–207 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Lobstein, T. et al. Child and adolescent obesity: part of a bigger picture. Lancet 385, 2510–2520 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Galvez, M. P. et al. Associations between neighborhood resources and physical activity in inner-city minority children. Acad. Pediatr. 13, 20–26 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Moore, J. B., Gunn, P. J. & Fielding, B. A. The role of dietary sugars and de novo lipogenesis in non-alcoholic fatty liver disease. Nutrients 6, 5679–5703 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Abdelmalek, M. F. et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 51, 1961–1971 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Stanhope, K. L. et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J. Clin. Invest. 119, 1322–1334 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vos, M. B. & Lavine, J. E. Dietary fructose in nonalcoholic fatty liver disease. Hepatology 57, 2525–2531 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Chung, M. et al. Fructose, high-fructose corn syrup, sucrose, and nonalcoholic fatty liver disease or indexes of liver health: a systematic review and meta-analysis. Am. J. Clin. Nutr. 100, 833–849 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lang, I. A. et al. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA 300, 1303–1310 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Trasande, L., Attina, T. M. & Blustein, J. Association between urinary bisphenol A concentration and obesity prevalence in children and adolescents. JAMA 308, 1113–1121 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Schwimmer, J. B. et al. Heritability of nonalcoholic fatty liver disease. Gastroenterology 136, 1585–1592 (2009).

    Article  PubMed  Google Scholar 

  107. Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Sookoian, S. & Pirola, C. J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease. Hepatology 53, 1883–1894 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Valenti, L. et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209–1217 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Trépo, E. et al. Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. Hepatology 59, 2170–2177 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Liu, Y. L. et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J. Hepatol. 61, 75–81 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Romeo, S. et al. The 148M allele of the PNPLA3 gene is associated with indices of liver damage early in life. J. Hepatol. 53, 335–338 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Santoro, N. et al. A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents. Hepatology 52, 1281–1290 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Rotman, Y. et al. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52, 894–903 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Trépo, E. et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease. J. Hepatol. 55, 906–912 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Trépo, E. et al. Impact of patatin-like phospholipase-3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. Hepatology 54, 60–69 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Stättermayer, A. F. et al. Hepatic steatosis in Wilson disease—role of copper and PNPLA3 mutations. J. Hepatol. 63, 156–163 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Speliotes, E. K. et al. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet. 7, e1001324 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Chalasani, N. et al. Genome-wide association study identifies variants associated with histologic features of nonalcoholic fatty liver disease. Gastroenterology 139, 1567–1576 (2010).

    Article  PubMed  Google Scholar 

  120. Tan, H. L. et al. Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene. J. Gastroenterol. 49, 1056–1064 (2014).

    Article  CAS  PubMed  Google Scholar 

  121. Aravinthan, A. et al. Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease. Cell Cycle 13, 1489–1494 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Al-Serri, A. et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies. J. Hepatol. 56, 448–454 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Wang, X., Liu, Z., Peng, Z. & Liu, W. The TM6SF2 rs58542926 T allele is significantly associated with nonalcoholic fatty liver disease in Chinese. J. Hepatol. 62, 1438–1439 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Liu, Y. L. et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat. Commun. 5, 4309 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Kozlitina, J., Boerwinkle, E., Cohen, J. C. & Hobbs, H. H. Dissociation between APOC3 variants, hepatic triglyceride content and insulin resistance. Hepatology 53, 467–474 (2011).

    Article  CAS  PubMed  Google Scholar 

  126. Zarrinpar, A., Gupta, S., Maurya, M. R., Subramaniam, S. & Loomba, R. Serum microRNAs explain discordance of non-alcoholic fatty liver disease in monozygotic and dizygotic twins: a prospective study. Gut http://dx.doi.org/10.1136/gutjnl-2015-309456.

  127. Barlow, S. E. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics 120 (Suppl. 4), S164–S192 (2007).

    Article  PubMed  Google Scholar 

  128. Chalasani, N. et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55, 2005–2023 (2012).

    Article  PubMed  Google Scholar 

  129. Loomba, R. et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study. Hepatology 60, 1920–1928 (2014).

    Article  CAS  PubMed  Google Scholar 

  130. Cui, J. et al. Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease: a prospective study. Aliment. Pharmacol. Ther. 41, 1271–1280 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Guo, S. S., Wu, W., Chumlea, W. C. & Roche, A. F. Predicting overweight and obesity in adulthood from body mass index values in childhood and adolescence. Am. J. Clin. Nutr. 76, 653–658 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Promrat, K. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 51, 121–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Vilar-Gomez, E. et al. Weight loss via lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology http://dx.doi.org/10.1053/j.gastro.2015.04.005.

  134. Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005).

    Article  PubMed  Google Scholar 

  135. Kistler, K. D. et al. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am. J. Gastroenterol. 106, 460–468 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Oh, S. et al. Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. Hepatology 61, 1205–1215 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Dudekula, A., Rachakonda, V., Shaik, B. & Behari, J. Weight loss in nonalcoholic fatty liver disease patients in an ambulatory care setting is largely unsuccessful but correlates with frequency of clinic visits. PLoS ONE 9, e111808 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Nobili, V. et al. Lifestyle intervention and antioxidant therapy in children with nonalcoholic fatty liver disease: a randomized, controlled trial. Hepatology 48, 119–128 (2008).

    Article  CAS  PubMed  Google Scholar 

  139. Grønbæk, H. et al. Effect of a 10-week weight-loss camp on fatty liver disease and insulin sensitivity in obese Danish children. J. Pediatr. Gastroenterol. Nutr. 54, 223–228 (2012).

    Article  PubMed  Google Scholar 

  140. Lavine, J. E. et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 305, 1659–1668 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Trauner, M., Claudel, T., Fickert, P., Moustafa, T. & Wagner, M. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig. Dis. 28, 220–224 (2010).

    Article  CAS  PubMed  Google Scholar 

  143. Fang, S. et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21, 159–165 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

    CAS  PubMed  Google Scholar 

  145. Sjöström, L. Review of the key results from the Swedish Obese Subjects (SOS) trial—a prospective controlled intervention study of bariatric surgery. J. Intern. Med. 273, 219–234 (2013).

    Article  PubMed  Google Scholar 

  146. Mathurin, P. et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology 137, 532–540 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Caiazzo, R. et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann. Surg. 260, 893–898 (2014).

    Article  PubMed  Google Scholar 

  148. Loy, J. J. et al. Improvement in nonalcoholic fatty liver disease and metabolic syndrome in adolescents undergoing bariatric surgery. Surg. Obes. Relat. Dis. 11, 442–449 (2015).

    Article  PubMed  Google Scholar 

  149. Nobili, V. et al. Indications and limitations of bariatric intervention in severely obese children and adolescents with and without nonalcoholic steatohepatitis: ESPGHAN Hepatology Committee Position Statement. J. Pediatr. Gastroenterol. Nutr. 60, 550–561 (2015).

    Article  PubMed  Google Scholar 

  150. Huang, T. T. et al. Assessing overweight, obesity, diet, and physical activity in college students. J. Am. Coll. Health 52, 83–86 (2003).

    Article  PubMed  Google Scholar 

  151. Nanney, M. S. et al. Weight and weight-related behaviors among 2-year college students. J. Am. Coll. Health 63, 221–229 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Slutske, W. S. Alcohol use disorders among US college students and their non-college-attending peers. Arch. Gen. Psychiatry 62, 321–327 (2005).

    Article  PubMed  Google Scholar 

  153. Hiramine, Y. et al. Alcohol drinking patterns and the risk of fatty liver in Japanese men. J. Gastroenterol. 46, 519–528 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. Dunn, W., Xu, R. & Schwimmer, J. B. Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease. Hepatology 47, 1947–1954 (2008).

    Article  PubMed  Google Scholar 

  155. Tarantino, G., Citro, V. & Finelli, C. Recreational drugs: a new health hazard for patients with concomitant chronic liver diseases. J. Gastrointestin. Liver Dis. 23, 79–84 (2014).

    PubMed  Google Scholar 

  156. Bailey, J. A., Fleming, C. B., Henson, J. N., Catalano, R. F. & Haggerty, K. P. Sexual risk behavior 6 months post-high school: associations with college attendance, living with a parent, and prior risk behavior. J. Adolesc. Health 42, 573–579 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Lowry, R., Robin, L., Kann, L. & Galuska, D. A. Associations of body mass index with sexual risk-taking and injection drug use among US high school students. J. Obes. 2014, 816071 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  158. American Academy of Pediatrics. et al. Supporting the health care transition from adolescence to adulthood in the medical home. Pediatrics 128, 182–200 (2011).

  159. Vajro, P., Ferrante, L., Lenta, S., Mandato, C. & Persico, M. Management of adults with paediatric-onset chronic liver disease: strategic issues for transition care. Dig. Liver Dis. 46, 295–301 (2014).

    Article  PubMed  Google Scholar 

  160. Schwartz, L. A., Tuchman, L. K., Hobbie, W. L. & Ginsberg, J. P. A social-ecological model of readiness for transition to adult-oriented care for adolescents and young adults with chronic health conditions. Child Care Health Dev. 37, 883–895 (2011).

    Article  CAS  PubMed  Google Scholar 

  161. Schwartz, L. A. et al. Stakeholder validation of a model of readiness for transition to adult care. JAMA Pediatr. 167, 939–946 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank M. Salamao for providing the images of NAFLD used in this paper. A.A.M., R.L. and J.E.L. are supported by NIH U01DK61734.

Author information

Authors and Affiliations

  1. Division of Paediatric Gastroenterology, Hepatology and Nutrition, Columbia University Medical Centre, 622 West 168th Street, New York, 10032, NY, USA

    Ali A. Mencin & Joel E. Lavine

  2. Division of Gastroenterology, University of California at San Diego, 9500 Gilman Drive, La Jolla, 92093, CA, USA

    Rohit Loomba

Authors
  1. Ali A. Mencin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rohit Loomba
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joel E. Lavine
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.A.M. researched data for the article. All the authors substantially contributed to discussion of content, wrote the article, and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Joel E. Lavine.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mencin, A., Loomba, R. & Lavine, J. Caring for children with NAFLD and navigating their care into adulthood. Nat Rev Gastroenterol Hepatol 12, 617–628 (2015). https://doi.org/10.1038/nrgastro.2015.146

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrgastro.2015.146

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing